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77 Cards in this Set
- Front
- Back
Structure of proteins:
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1. Polymers of aminoacids
2. Macromolecules (Mr > 10 000) |
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Amino acids in proteins:
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1. L-α-aminocarboxylic acids (Amino group on the left side)
2. There are 21 proteinogenic AAs 3. The rest of the AAs are formed by posttranslational modifications. |
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Non-polar group of amino acids:
1. Characteristics 2. Names |
1. Hydrophobic
2. Ala, Val, Leu, Ile, Pro, Phe, Trp, Met |
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Polar group of amino acids:
1. Characteristics 2. Names |
1. Hydrophilic (non- charged)
2. Gly, Ser, Thr, Cys, Tyr, Asn, Gln |
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Acidic group of amino acids:
1. Characteristics 2. Names |
1. Negatively charged
2. Asp, Glu |
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Basic group of amino acids:
1. Characteristics 2. Names |
1. Positively charged
2. Lys, Arg, His |
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Modified amino acids:
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1. 4- Hydroxyproline
2. 3- Hydroxyproline 3. 5- Hydroxylysine 4. Allysine |
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Essential amino acids (grouped);
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1. Branched chain AAs: Val, Leu, Ile
2. Aromatic AAs: Phe, Trp 3. Basic AAs: His, Arg, Lys 4. Sulfur- containing AAs: Met 5. Other: Thr |
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What determines the final properties of amino acids:
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The side chains
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1. What is the Isoeletric point (pI):?
2. Formula: |
1.The pH value at which the net charge of the compound is zero
2. pI= pKCOOH+ pK NH3/ 2 |
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What are AA solution called called and what is the charge under physiological conditions?
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Ampholytes (amphoteric electrolytes). Are negatively charged under physiological conditions.
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Properties of AAs:
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1. UV radiation absorbtion
2. Ability to bind other compounds (phosphate or saccharide) 3. Can form disulfide bonds |
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Important reactions of AAs:
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1. Dissociation--> salts
2. Decarboxylation--> bioenic amines 3. Transamination--> 2-oxoacids 4. Oxidative deamination--> 2- oxoacids 5. Formation of peptide bonds---> peptides/ proteins |
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Nr. of AAs:
1. Oligopeptides 2. Polypeptides 3. Proteins |
1. 2-10AAs
2. >10 AAs 3. Proteins: About 50> AAs. Polypeptides of Mr > 10 000 |
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Peptide bond:
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Condensation of an N and C terminal from 2 AAs. Removal of H2O (O from COO- and H2 from NH3+)
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Bonds found in proteins:
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1. Covalent: Peptide bonds and disulfide bonds
2. Noncovalent interactons: Hydrogen bonds, hydrophobic interactions between nonpolar side chains and ionic interactions |
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Primary structure of proteins:
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1. The order of amino acids
2. Read from N- to C- 3. Coded on a genetic level 4. Stabilized by peptide bonds |
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Secondary structure of proteins:
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1. Spatial arrangement of the polypeptide chain given by rotation of the planar peptide bonds around α- carbons
2. Stabilized by hydrogen bonds between -CO- and -NH- of the peptide bonds 3. Different parts of the polypeptide chain exist in various secondary structure |
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Helical structure:
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1. Various types of spiral: Different steepness, direction of rotation, and number of AAs per turn
2. Peptide bonds are parallel to the axis of the helix with R- perpendicular to it 3. H- bonds are formed between AAs found above and below themselves 4. α- helix is right handed, collagern helix is left handed and steaper |
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β- plated sheet:
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1. Parallel or antiparallel
2. R- groups are placed above or below the sheet 3. H- bonds are formed between peptide bonds of the neighboring parts of the polypeptide chain 4. Function: brings strength to proteins |
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Tertiary structure of proteins:
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1. Consists of spatial arrangement of secondary structure which are folded into domains
2. Stabilization between side chains of AAs: - Hydrogen bonds - Ionic interactions - Hydrophobic interactions - Disulfide bonds |
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Classification of proteins according to their structure:
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1. Globular: Spheroidal shape, both secondary structures are abundant
2. Fibrous proteins: rod like shape, one secondary structure predominates, e.g. alfa- keratin, collagen |
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Quaternary structure of proteins:
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1. Oligomeric structure (2 or more subunits)
2. Stabilized by noncovalent interactions 3. Proteins have an allosteric effect |
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Classification of proteins:
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1. By localization in an organism: intra-/ extracellular
2. By function: structural/ biological active 3. By shape: globular/ fibrous 4. By chemical composition: simple/ complex (conjugated proteins) |
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What does conjugated proteins contain:
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Polypeptide chain+ prosthetic group
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Physiochemical properties of proteins:
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1. Solubility depends on structure
2. Proteins form colloidal solutions= oncotic pressure 3. Can be denaturated by heat, radiation, strong pH changes, salts of heavy metals, organic solvents |
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Protein determent in laboratory:
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1. Chemical reactions of peptide bonds with biuret reagent- spectophotometry
2. Complementary reaction with an antibody- immunochemistry 3. Separation in an electric field: electrophoresis |
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Sources of AAs:
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1. Diet
2. Synthesis de novo 3. Protein degradation |
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Conditionally essentiel AAs:
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Histidine and Arginine
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5 substrates for synthesis of AAs in a human body:
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1. Oxaloactetate--> Asp, Asn
2.α- ketoglutarate---> Glu, Gln, Pro, Arg 3. Pyruvate--> Ala 4. 3-phosphoglycerate---> Ser, Cys, Gly 5. Phe---> |
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Transamination:
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1. A reversible exchange of - NH2 between amino acid and a α- ketoacid
2. Catalyzed by transaminases (most of the require α-ketoglutarate as an amino acceptor 3. Coenzyme of transaminases: pyroxidal phosphate |
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Important aminotransfers:
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1.Glutamate+ α- keto acid--><---- α- ketoglutarate+ α- amino acid
2. Glutamate+ pyruvate= Alanine + α- ketoglutarate |
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Amidation of glutamate:
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The side chain of carboxylic acid group is converted to amide group by adding of a ammonia group by the energy of ATP catalyzed by glutamine synthetase---> Glutamine ( the most important transport form of amino nitrogen in blood.
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Synthesis of aspargine:
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Aspartate+ Glutamine + ATP---> Aspargine+ Glutamate
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Synthesis of thyrosine:
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Phenylalanine is hydroxylated by Penylalanine hydroxylase while H2- biopterin is reduced by Dihydropteridine reductase to H4- biopterin while NADH is oxidized.
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Formation of activated methionine:
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Methionine + ATP (catalyzed by methionine adenosyltransferase)----> S- adenosylmethionine (SAM).
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What is the metabolic function of SAM (S-adenosylmethionine)?
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To function as a methyl group donor in metabolic methylations
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AAs used for synthesis of other N- compounds:
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1. Gln, Asp, Gly----> purines, pyrimidines
2. Gly---> porphyrines, creatine (+Arg and Met) 3. Arg--> NO 4. Cys--> taurine |
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Decaroboxylation of AAs gives monoamines (biogenic amines):
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1. Tyr---> catecholamines
2. His---> histamine 3. Ser---> etanolamine---> choline -->acetylcholin 4. (Cys--> cysteamine, Asp--> β- alanine) ---> coenzyme A 5. Glu---> GABA |
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3 main steps of catabolism of AAs:
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1. Removing of NH2 group form AAs
2. Detoxification of the amino group 3. Metabolism of carbon skeleton from AAs Catalyzed by 20 different multi enzyme sequences |
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All 20 AAs are converted to only 7 compounds:
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1. Pyruvate (both)
2. Acetyl- CoA (ketogenic) 3. Acetoacetyl- CoA (ketogenic) 4. α- ketoglutarate 5. Succinyl- CoA (both) 6. Fumarate (both) 7. Oxaloacetate |
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Ketogenic AAs:
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1. Leucine
2. Lysine |
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Both ketogenic and glucogenic AAs:
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1. Isoleucine
2. Threonine 3. Phenylalanine 4. Tyrosine 5. Tryptophan |
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Deamination:
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1. E.g glutamate:
Glutamate is oxidated by glutamate dehydrogenase while NAD+ is reduced, releasing NH4+ and producing α- ketoglutarate. NH4+ enter the urea cycle and α- ketoglutarate enter citric cycle or another transamination |
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Examples of decarboxylation reactions:
(Product is amines!!) |
1. Histidine---> histamine by Histidine decarboxylase
2. Trp---> serotonin 3. Tyr----> adrenalin and noradrenalin 4. Glu---> GABA |
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What process happen where:
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1. In extrahepatic tissue:
- Transamination - Deamination - Amidation 2. In the liver: - Oxidative deamination |
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Ammonia transport and detoxification:
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Ammonia is mainly transported by glutamine to liver mitochondria where glutaminase with the help of H2O cleaves and releases NH4 to the urea cycle and glutamate then glutamate can be oxidatively deaminated releasing the other ammonium to the urea cycle.
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Glucose- Alanine cycle:
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1. Glucose is degraded to pyruvate by glycolysis in extrahepatic tissues which undergoes transamination with glutamate from AAs----> α- ketoglutarate and Alanine. Catalyzed by "alanine transaminase"
2. Alanine is transported in blood to the liver where there is a transamination between alanine and α- ketoglutarate--> pyruvate and glutamate (alanine transaminase). 3. Pyruvate undergoes gluconeogenesis---> glucose which is transported back to extrahepatic tissues--> glycolysis 4. Glutamate undergoes oxidative deamination catalyzed bye "glutamate dehydrogenase"---> α- ketoglutarate and NH4+ 5. NH4 + enters urea cycle and α- ketoglutarate can either enter citric acid cycle or undergo another transamination. |
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1. Glutamine synthetase catalyze:
2. Glutaminase catalyze: |
1.Glutamate+ NH4+ + ATP---> glutamine+ ADP+ Pi
2. glutamine+ H2O---> glutamate+ NH4+ (in kidneys) |
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Glutamate dehydrogenase:
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1. Removes amino group from glutamate in liver while NAD+ is reduced---> α- ketoglutarate and NH4+
2. The - NH2 from AAs was transferred by transamination |
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Urea (ornithine cycle)
1. Why? 2. Location in body and cell: 3. Substartes and products: 4. Regulatory enzyme: 5: Negative consequence?? 6. Energy requirements: |
1. NH3 exists as NH4+ which can change membrane potensials and inhibit action potensials
2. Mitochondria and cytosol of liver cells 3. Substrates: NH4+, CO2 and HCO3-. Product: urea---> urine 4. Carbamoyl phosphate synthase (allosteric activator: N- acetylglutamate) 5. Consumes HCO3- ---> decreased buffer capacity----> acidosis 6. 3 ATP and 4 energy rich bonds from fumarate |
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Urea cycle gets NH4+ from:
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1. Glutamate by glutamate dehydrogenase
2. Glutamine by glutaminase |
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Urea cylce:
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1. Matrix: CO2+ 2ATP+ NH3+ (Carbampyl phosphate synthetase 1)---> Carbamoyl phosphate+ 2ADP+ P
2. Carbamoyl gets transferred to Ornithine by Ornithine carbamoylase, releasing P----> L- Citrulline 3. Citrulline is transported to the cytosol where aspartate is added---> Argininosuccinate (argininosuccinate synthaze), consuming 1 more ATP (3total) 4. Argininosuccinate is cleaved by (argininosuccinate lyase)---> Fumarate + L- Arginine (containing the nitrogens) 5. Arginine is cleaved by (arginase with H2O)---> Urea + Ornithine (which can enter back into the matrix and undergo the cycle once again |
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How is the urea cycle regulated?
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1. Allosteric regulation
2. Enzyme induction by protein rich diet or by metabolic changes during starvation |
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Regulatory enzymes of urea cycle?
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1. Carbamoyl phosphate synthase 1 (mitochondrial) is activated by N- acetylglutamate.
2. N- acetylglutamate synthetase is activated by arginine |
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What inhibits urea cycle?
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Acidosis inhibits urea cycle because HCO3- is saved to buffer the acidosis instead of being wasted in urea synthesis
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Important notes about synthesis of purines:
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1. Location: cytoplasm
2. PRPP (phosphoribosyl pyrophosphate) provides the ribose phosphate for purine synthesis. Derived from ribose-5-P----> a set of steps until --> IMP 3. IMP: inosine monophosphate common precursor of AMP and GMP 4. Glutamine, Glycine and Aspartate donate C and N atoms 5. CO2 donates C 6. C1 units are transferred via tetrahydrofolate 7. Regulatory enzyme: Glutamine: PRPP amidotransferase: activated by PRPP and inhibited by AMP and GMP |
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Salvage pathway:
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Purines from normal turnover of cellular NA can be converted to nucleoside triphosphates
E.g: Hypoxanthine---> IMP, Guanine---> GMP, Adenine----> AMP Substrates: purine bases, PRPP, ATP |
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Important enzymes in synthesis of purine nucleotides:
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1. Glutamine- PRPP amidotransferase: catalyze first step where PRPP---> 5- phosphoribosylamine where glutamate donates NH2 and becomes glutamate
2. Adenylsuccinate lysase: hydrolyses and releases fumarate |
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Degradation of purine nucleotides:
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1.Uric acid is formed by enzyme xanthine oxidase
2. GMP--> Guanosine--> Guanine--> (xanthine oxidase) Xanthine---> (xanthine oxidase)---> Urate 3. AMP---> (adenylate deaminase) IMP--> Inosine---> Hypoxanthine---> (xanthine oxisase) xanthine---> (xanthine oxidase) Urate |
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Important notes about pyrimidine nucleotides synthesis:
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1. First step: Carbamoyl phosphate is formed from Glutamine, 2 ATP and CO2 (catalyzed by carbamoyl- P synthetase II)
2. Above mentioned enzyme is inhibited by UTP and activated by PRPP. 3. Carbamoyl phosphate + aspartate---> Carbamoyl aspartate---> Dihydroorotate---> Orotate---> OMP---> UMP---> UTP--> CTP. 4. dUMP can be converted to dTMP by thymidylate synthase |
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Ribonucleotide reductase:
1. Function: 2. Structure: 3. Regulation: |
1. Conversion of ribonucleotides to deoxynucleotides
2. Composed of two nonidentical dimeric subunits: R1 and R2 and two sulfhydryl groups on the enzyme which are donors of Hydrogens needed for reduction of 2`hydroxyl groups. Form disulfide bonds 3. Activated by ATP, inhibited dATP. |
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Degradation of pyrimidine bases:
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The pyrimidine rings are are reduced by NADPH oxidation and opened----> β- aminoacids are formed (β- alanine and β- aminoisobutyrate) and CO2 and NH4+ released
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Tetrapyrrols:
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1. Circular compounds binding a metal ion (most frequently Fe2+ or Fe3+)
2. Consists of 4 pyrrol rings interconnected via methenyl bridges (porphyrins) 3. Contain side chain attached to each of the 4 pyrrole rings 4. Examples: - Heme (Fe2+) - Chlorophyll (Mg2+) - Vitamin B12 (Co2+) |
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Where can we find heme?
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1. Hemoglobin
2. Myoglobin 3. Cytochrome C 4. Catalases |
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Biosynthesis of heme:
1. Organ location: 2: Subcellular location 3. Substrates: 4. Important intermediates: 5: Key regulatory enzyme: |
1. 85% bone marrow, rest in liver
2. Mitochondria and cytosol 3. Succinyl- CoA and glycine 4. δ- aminolevulinic acid (ALA), porphobilinogen , uroporphyrinogen III, protoporphyrin IX 5. ALA synthase (inhibited by Heme and Iron) |
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Heme synthesis:
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1. Mitochondria: Succinyl- CoA and glycine condensate----> δ- aminolevulinic acid (ALA) catalyzed by ALA synthase, releasing CO2 and CoA- SH
2. ALA leaves cytoplasm where 2 ALA molecules condense---> porhobilinogen (catalyzed by porhobilinogen synthase) releasing 2 H2O 3. 4 porphobilinogen molecules links and cleaves of 4 NH4+---> uroporphyrinogen III 4. 4 acetate residues are decarboxylated into methyl groups---> coproporphyrinogen III which returns to the mitochondria 5. Coproporphyrinogen--> Protoporphyrinogen IX 6. Oxidation of Protoporphyrinogen IX---> Protoporphyrin IX 7. Fe2+ is incorporated into protoporphyrin IX (catalyzed by ferrochelatase)---> Heme |
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Regulation of heme synthesis:
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1. ALA synthase is an allosteric enzyme inhibited by heme by feedback inhibition
2. ALA synthase requires pyridoxal phosphate 3. Certain steroid hormones and drugs can increase heme synthesis 3. Porphobilinogen synthase and ferrochelatase is inhibited by lead ions (lead poisoning) |
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Porphyrias:
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1. Hereditary disturbances of heme synthesis
2. Abnormality of enzymes in heme synthesis----> accumulation of intermediates and a deficiency of heme---> excretion of heme precursors in urine (dark red color) 3. Accumulation of porphyrinogens in skin---> photosensitivity 4. Neurological symptoms 5. Treatment: Injection of hemin: supplements heme and inhibits transcription of ALA- synthase |
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Heme degradation:
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1. Erythrocytes are degraded in reticuloendothelial cells in spleen, liver and bone marrow.
2. Hb is degraded to: - Globin--> AAs---> metabolism - Heme---> Bilirubin - Fe2+--> transported with transferrin and used in the next heme biosynthesis |
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Conversion of heme to bilirubin:
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1. Heme is reduced and O2 is added while NADPH is oxidized. (Catalyzed by heme oxygenase) releases CO+ Fe3+ + NADP----->Biliverdin
2. Biliverdin is reduced to Bilirubin by "Biliverdin reductase" while NADPH is oxidized |
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Fate of Bilirubin:
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1. Bilirubin is released by RES to blood and transported by albumin to liver.
2. In the hepatocytes bilirubin is conjugated with two molecules of glucuronic acid---> bilirubin diglucuronide which is soluble. (Catalyzed by UDP- glucuronosyltransferase) 3. Bilirubin diglucuronide---> bile---> intestine 4. Bacteria reduces Bilirubin diglucuronide---> urobilinogen. 5. Uribilinogen is oxidized by intestinal bacteria to stercobilin which is secreted by feces 6. Some urobilinogen is transported by blood to kidneys where it is oxidized to urobilin and excreted by urine |
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Determation of bilirubin in serum:
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Conjugated bilirubin reacts directly with dyes, free bilirubin reacts only when there is methanol or caffeine in the solutine and are therefore indirect.
Total bilirubin: <20micromol/L |
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Hyperbilirubinemias:
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1. > 10mg/L---> Bilirubin diffuses from blood to peripheral tissues---> jaundice
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Causes of jaundice:
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1. Hemolytic jaundice: Increased erythrocyte degradation
2. Hepatocellular jandice: Impaired conjugation in the liver (liver damage) 3. Obstructive jaundice: Disturbance of bile drainage (gallstones) (Only conjugated bilirubin can be present in urine) |
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Icterus
1. What? 2. Two types: |
1. Yellow coloration of skin and mucus due to jaundice
2. - Hemolytic icterus: Elevated levels of unconjugated bilirubin in blood - Neonatal jaundice: Elevated hemolysis, decreased activity of UDP- glucuronsyltransferase--> Elevated unconjugated bilirubin (happens a few days after birth |
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Kernicterus:
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Severe cases of jaundice where unconjugated bilirubin cross the blood brain barrier causing brain damage
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